Studies of families with neurofibromatosis type 1 (NF1) have demonstrated that the severity of this disease depends on modifier genes in the individuals. We are using a mouse model of the malignancies associated with NF1 in which the Nf1 and p53 gene are mutated on the same chromosome and screening for modifier genes in different strains of mice. Importantly, both Nf1 and p53 are mutated in sporadic forms of glioblastoma and sarcoma, thus the understanding of tumor mechanisms gained from this project may have relevance to sporadic nervous system tumors and well as NF1. Using a combination of mouse genetics and expression profiling in tumors, we have recently identified a region responsible for resistance to developing malignant peripheral nerve sheath tumors (MPNSTs) in one strain of mice, and another region responsible for susceptibility to astrocytoma. We have identified a candidate modifier gene on mouse chromosome 11 affecting MPNST susceptibility, and are working to identify additional candidate modifier genes on other chromosomes. These candidate modifiers will then be tested for their role in tumorigenesis in our mouse model and then in human cancers. During fiscal year 2010, we have tested expression and splicing differences in several candidate modifiers affecting MPNSTs and have found strain-specific differences in several. We have extended our finding that an imprinted gene on mouse chromosome 11 acts in a haploinsufficient, tumor suppressive manner when mutated in our model system. Further study of this gene in the upcoming years may elucidate the mechanism of inherited susceptibility/resistance. We have also used genetic methods to narrow the modifier region on mouse chromosome 19, reducing the length of the region to approximately one half its original size. We are continuing to refine the mapped location of the modifier locus and are concurrently testing candidate genes in the region. To identify modifiers of astrocytoma, we have completed the phenotyping and genotyping of 600 backcross mice to identify modifier loci affecting resistance in the 129 strain background. This data has now been completely collected and has been sent to our biostatistician collaborator at the University of Wisconsin, and we are awaiting the completion of the analysis.